US20060263346A1 - Combined pharmaceutical preparations for the treatment of cancer, containing glutaminase and antineoplastic anthracyclines or platinum compounds - Google Patents

Combined pharmaceutical preparations for the treatment of cancer, containing glutaminase and antineoplastic anthracyclines or platinum compounds Download PDF

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Publication number
US20060263346A1
US20060263346A1 US10/560,317 US56031704A US2006263346A1 US 20060263346 A1 US20060263346 A1 US 20060263346A1 US 56031704 A US56031704 A US 56031704A US 2006263346 A1 US2006263346 A1 US 2006263346A1
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Prior art keywords
glutaminase
compound
preparation
activity
cancer
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US10/560,317
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Frank Leenders
Seifert Wenke
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New Medical Enzymes AG Research & Development
Medical Enzymes AG
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Medical Enzymes AG
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Publication of US20060263346A1 publication Critical patent/US20060263346A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention concerns combined pharmaceutical preparations which inhibit the abnormal growth of tumor cells. These combined preparations contain compounds as active substances which have glutaminase activity in combination with certain antineoplastic agents.
  • the invention concerns combined preparations of compounds having glutaminase activity and cytostatic compounds.
  • cancer embraces a large number of malignant diseases which are characterized by uncontrolled cell growth, lack of cell differentiation and penetration of neighbouring tissue and the formation of metastases. Almost any tissue can be the origin of such a malignant disease.
  • antineoplastic agents involve considerable disadvantages and risks for the patients despite their advanced state of development. Due to their unspecific antiproliferative effect and the high doses, these antineoplastic agents do not only damage tumor cells but also healthy rapidly growing cells such as mucous membranes, haematopoietic cells (bone marrow) and hair follicles. Treatment with antineoplastic agents is usually associated with severe side-effects which impair the general well-being of patients (acute side-effects), it also results in irreversible damage to healthy tissue and increases the risk of secondary tumors. Furthermore, the tumors may become resistant to the agents which results in a loss of efficacy when they are used several times on a patient.
  • Glutamine is the most frequent amino acid in the blood circulation and plays a major role as a source of nitrogen and energy as well as a basic component for many endogenous syntheses. Tumor cells are especially dependent on glutamine from the blood circulation due to their strong growth.
  • the object of the present invention was therefore to increase the effect of antineoplastic agents and to provide preparations that can be used in concentrations which cause no or only slight toxicity and antibody formation.
  • antineoplastic agents in combination with compounds having glutaminase activity are suitable for achieving this object.
  • the combinations act synergistically and are directly or indirectly toxic for dividing cells and can thus be used for an antineoplastic therapy.
  • the components having glutaminase activity act as amplifiers which lower the required dose of antineoplastic agents and reduce the side effects as well as the late sequelae.
  • Platinum complexes and in particular cis-platinum, oxaliplatinum, carboplatinum or derivatives thereof or anthracyclines and in particular doxorubicin or daunomycin or derivatives thereof are used as antineoplastic agents.
  • the invention concerns in particular combined preparations of compounds having glutaminase activity and cytostatic compounds.
  • Cytostatic agents have already for a long time been a recognized and widely used treatment concept in antineoplastic therapy. They are used to destroy malignant cells having an uninhibited growth behaviour. Normal and healthy cells should be damaged as little as possible.
  • compounds which have glutaminase activity are understood as the proteins or enzymes: glutaminase, glutaminase-asparaginase, glutaminase analogues, derivatives and modifications thereof which either occur naturally or are produced synthetically and inhibit glutamine production.
  • the compounds can be modified or provided with protective substances.
  • Compounds modified with polyethylene glycol are preferably used.
  • Glutaminase produced by genetic engineering or/and Pseudomonas glutaninase are particularly preferred.
  • Glutaminases which are preferred according to the invention are described in WO 94/13817.
  • Antineoplastics are understood as substances which are suitable for and are used to damage or destroy microorganisms, parasites or tumor cells. These include in particular cytostatic agents or derivatives thereof from the following groups:
  • the present invention concerns the use of antineoplastic agents together with compounds having glutaminase activity to treat cancer and other diseases that are associated with abnormal cell proliferation.
  • Such combinations of active substances are composed in particular of a glutaminase-asparaginase, preferably Pseudomonas 7A glutaminase-asparaginase and one or more antineoplastic agents from the above-mentioned groups.
  • Combinations of this invention are characterized by the fact that the antitumoral effect of conventional antineoplastic agents is significantly amplified by combining them with a compound having glutaminase activity and that the active protein ingredient can itself be used in concentrations that do not cause any toxic effects.
  • the combined preparations can be used for cancer therapy.
  • subtherapeutic doses of a compound having glutaminase activity and antineoplastic agents which synergistically inhibit tumor cell growth This means that the combination of active substances has a substantially higher antineoplastic activity than an active substance of this class of active substances would have alone.
  • Antineoplastic agents that are suitable for a combination include according to the invention platinum complexes and in particular cis-platinum, oxaliplatinum, carboplatinum or derivatives thereof, as well as anthracyclines e.g. actinomycin D, mitoxantrone and in particular the DNA intercalators doxorubicin and daunomycin (daunorubicin).
  • platinum complexes and in particular cis-platinum, oxaliplatinum, carboplatinum or derivatives thereof, as well as anthracyclines e.g. actinomycin D, mitoxantrone and in particular the DNA intercalators doxorubicin and daunomycin (daunorubicin).
  • antineoplastic agents that can be used for a combination include the DNA-alkylating agents clyclophosphamide, ifosfamide, melphalane, the antimetabolites methotrexate, 5-fluoruracil, the spindle or microtubuli toxins vincristine, vinblastine, paclitaxel; the topoisomerase inhibitor etoposide; the antibiotics actinomycin D, mitomycin, mitoxantrone, the hormones tamoxifen and flutamide.
  • the advantage of using a combined therapy with the aid of the pharmaceutical preparations of the present invention is the synergistic amplification of the antitumoral efficacy of the individual substances. This also allows a reduction of the doses and thus of the toxicity of the individual substances while at the same time retaining the antitumoral effectiveness when combining the individual substances.
  • a combination treatment comprising the above-mentioned individual therapy principles also enables cytostatic resistances to be overcome in which case resistances to groups of substances as well as multiple resistances (pleiotropic cytostatic agent resistance) come into question.
  • Alkylating cytostatic agents such as platinum preparations have an effect on cancer cells especially during cell division.
  • Energy depletion due to glutamine removal by glutaminase as well as the absence of glutamine for DNA synthesis due to glutaminase results in a prolongation of the cell division time and thus to a prolongation of the phase in which the cancer cells are vulnerable to alkylating substances.
  • the active substances can be processed into solid pharmaceutical preparations by conventional processes in which for example both active substances are mixed together and pressed for example into tablets together with common carrier substances or auxiliary substances. It is, however, also possible to provide the active substances separately in a packaging unit that is ready for sale where the packaging unit contains the two active substances in separate pharmaceutical formulations.
  • the injection solutions can already contain the relevant combinations of active substances in a dissolved form that is ready to be injected. Basically it is, however, also possible to provide a parenteral formulation for each relevant active substance in a packaging unit such that the injection solutions can optionally be administered separately from one another. This form of application is the preferred method when the active substances are incompatible with one another.
  • the active substances can also be present in bulk for example in a lyophilized form, optionally together with common pharmaceutical auxiliary substances and be reconstituted or solubilized by adding common pharmaceutical injection media.
  • the pharmaceutical preparations can be used in a liquid or solid form for enteral or parenteral administration.
  • all conventional forms of administration come into consideration such as tablets, capsules, dragees, syrups, solutions and suspensions.
  • Water is preferably used as an injection medium which contains the usual additives for injection solutions such as stabilizers, solubilizers and buffers.
  • additives are for example tartrate and citrate buffer, ethanol, complexing agents such as ethylenediamine tetraacetic acid and non-toxic salts thereof as well as high-molecular polymers such as liquid polyethylene oxide to regulate the viscosity.
  • Liquid vehicles for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid vehicles are for example starch, lactose, silicic acids, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers such as polyethylene glycols; preparations suitable for oral administration can if desired contain flavouring agents or sweeteners.
  • the dosage depends on various factors such as mode of administration, species, age and individual condition.
  • the doses that are to be administered daily are 0.005-100 mg/kg body weight per individual component.
  • the ratio of the active substances can vary over a very wide range.
  • molar ratios between 1:10 to 1:1000 and 10:1 to 1000:1 are possible depending on the efficacy of the relevant active substances.
  • a ratio between 1:100 and 100:1 is preferred.
  • the present invention concerns a combined pharmaceutical preparation comprising at least one compound having glutaminase activity and at least one platinum complex and in particular cis-platinum. It was found that platinum complexes in a combination with glutaminase and in particular pseudomonas glutaminase exhibit synergistic effects on various tumor cell lines in tissue cultures of up to a factor of 120. The dose of cis-platinum and glutaminase can consequently each be considerably reduced compared to the doses required for single treatments. Thus the therapeutic dose for glutaminase in the combined preparations according to the invention is preferably 50-150 I.U./m 2 and in particular 100-130 I.U./m 2 .
  • the dose of platinum complex and in particular cis-platinum in the combined preparations according to the invention is preferably 1-20 mg/m 2 and in particular 2-15 mg/m 2 and even more preferably 5-10 mg/m 2 . With such dosages solid tumors are already observed to respond after five days administration.
  • the dose for a three week administration is preferably 10-100 mg/m 2 and in particular 20-50 mg/m 2 .
  • the dose of glutaminase is again preferably 50-150 I.U./m 2 and in particular 100-130 I.U./m 2 body surface.
  • the amount of doxorubicin is advantageously 1-20 mg/m 2 and in particular 2-15 mg/m 2 and even more preferably 5-10 mg/m 2 body surface for a once weekly administration.
  • the preferred dose is 5-60 mg/m 2 and in particular 10-50 mg/m 2 and even more preferably 15-30 mg/m 2 body weight.
  • the tumor cells were cultured in RPMI 1640 medium containing 7.5% foetal calf serum at 37° C. and 5% CO 2 . After the cells had grown for 24 hours, they were incubated with the substances to be tested for 48 hours. Mixtures without active substances served as controls and the blank value was determined before adding the active substances.
  • the antineoplastic agents used for the experiments were obtained from Sigma in cell culture quality.
  • a Pseudomonas 7A glutaminase-asparaginase modified with polyethylene glycol (DE 41 40 003 A1, WO 94/13817 A1 and WO 02/31498 A2) was used as the glutaminase.
  • FIG. 1 The anti-tumoral effect of 0.026 ⁇ g/ml mitomycin on cells of a CNS tumor (SF-539) and breast (MCF7) tumor alone and in combination with 0.001 U/ml glutaminase is shown in FIG. 1 .
  • Mitomycin alone has no effect on CNS cells; in combination with glutaminase the growth is reduced by 7% in comparison with the control.
  • Mitomycin reduces the growth of cells of the breast tumor MCF7 to 66% compared to the control. The growth is reduced to 40% by combination with 0.001 U/ml glutaminase.
  • FIG. 2 The anti-tumoral effect of 0.3 ⁇ g/ml mitoxantrone on cells of a breast (MCF7), lung (NCI-H460) and colon (SW-60) tumor alone and in combination with 0.001 U/ml glutaminase is shown in FIG. 2 .
  • Glutaminase alone only has a slight effect on the three tumors.
  • Mitoxantrone alone reduces the tumor cell growth to 23% to 47%. In the combination growth of cells of the breast, lung and colon tumor is reduced to 1%, 9% and 25% respectively.
  • FIG. 3 The anti-tumoral effect of 2 ⁇ g/ml cis-platinum on the cells of a lung (A549), breast (MCF7) and colon (HAT29) tumor alone and in combination with 0.001 U/ml glutaminase is shown in FIG. 3 .
  • Cis-platinum alone reduces the growth to 41%, 86% and 65% respectively.
  • glutaminase In combination with glutaminase the growth of the tumor cells is reduced to 15%, 18% and 2% respectively.
  • FIG. 4 The anti-tumoral effect of 2.3 ⁇ g/ml etoposide on the cells of a lung (A549 and NCl-1-123) and breast (MCF7) tumor alone and in combination with 0.001 U/ml glutaminase is shown in FIG. 4 .
  • Etoposide alone reduces the growth of these cells to about 40% compared to the control.
  • glutaminase In combination with glutaminase the growth of the tumor cells is reduced to 18% and 6% and 26% respectively.
  • FIG. 5 The anti-tumoral effect of 68 ⁇ g/ml melphalan on the cells of a lung (NCI-H23) tumor alone and in combination with 0.001 U/ml glutaminase is shown in FIG. 5 .
  • Melphalan reduces the tumor growth to 34%. In combination with glutaminase the growth is reduced to 10%.
US10/560,317 2003-06-11 2004-06-11 Combined pharmaceutical preparations for the treatment of cancer, containing glutaminase and antineoplastic anthracyclines or platinum compounds Abandoned US20060263346A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10326821.9 2003-06-11
DE10326821A DE10326821A1 (de) 2003-06-11 2003-06-11 Pharmazeutische Kombinationspräparate zur Krebstherapie
PCT/EP2004/006320 WO2004108153A1 (de) 2003-06-11 2004-06-11 Pharmazeutische kombinationspräparate zur krebstherapie enthaltend glutaminase und antineoplastische anthracycline oder platinverbindungen

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US20060263346A1 true US20060263346A1 (en) 2006-11-23

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US (1) US20060263346A1 (de)
EP (1) EP1633394B1 (de)
JP (1) JP2006527232A (de)
AT (1) ATE350054T1 (de)
AU (1) AU2004244755B9 (de)
CA (1) CA2528897A1 (de)
DE (2) DE10326821A1 (de)
ES (1) ES2280972T3 (de)
WO (1) WO2004108153A1 (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168662B1 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8168661B2 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8173686B2 (en) 2006-11-06 2012-05-08 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8178564B2 (en) 2006-11-06 2012-05-15 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8465736B2 (en) 2006-05-10 2013-06-18 New Medical Enzymes Ag Glutadon
EP2047858A1 (de) * 2007-10-10 2009-04-15 Institut National De La Sante Et De La Recherche Medicale (Inserm) Kombinationsprodukte zur Krebsbehandlung
EP3092236B1 (de) 2014-01-06 2020-08-26 Rhizen Pharmaceuticals S.A. Neuartige glutaminaseinhibitoren

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US4955857A (en) * 1988-07-18 1990-09-11 Shettigar Udipi R Multi-enzyme bioreactor therapy for cancer
US5776458A (en) * 1990-12-05 1998-07-07 Pharmacia & Upjohn S.P.A. Anthracycline-conjugates
US6200754B1 (en) * 1998-03-19 2001-03-13 Variagenics, Inc. Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
US6271381B1 (en) * 1993-03-04 2001-08-07 Matsushita Electric Industrial Co., Ltd. Cocaine derivative, protein conjugate thereof, monoclonal antibody producing cell line, method for preparing the cell line and monoclonal antibody
US20020094542A1 (en) * 1988-04-15 2002-07-18 Peter Leskovar Drugs and methods for treating cancer

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US20020115609A1 (en) * 1997-07-14 2002-08-22 Hayat Onyuksel Materials and methods for making improved micelle compositions
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WO2003039545A2 (en) * 2001-11-07 2003-05-15 Millennium Pharmaceuticals, Inc. Carboline derivatives as inhibitors of ikb in the treatment of multiple myeloma and others cancers

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US20020094542A1 (en) * 1988-04-15 2002-07-18 Peter Leskovar Drugs and methods for treating cancer
US4955857A (en) * 1988-07-18 1990-09-11 Shettigar Udipi R Multi-enzyme bioreactor therapy for cancer
US5776458A (en) * 1990-12-05 1998-07-07 Pharmacia & Upjohn S.P.A. Anthracycline-conjugates
US6271381B1 (en) * 1993-03-04 2001-08-07 Matsushita Electric Industrial Co., Ltd. Cocaine derivative, protein conjugate thereof, monoclonal antibody producing cell line, method for preparing the cell line and monoclonal antibody
US6200754B1 (en) * 1998-03-19 2001-03-13 Variagenics, Inc. Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168662B1 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8168661B2 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8173686B2 (en) 2006-11-06 2012-05-08 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8178564B2 (en) 2006-11-06 2012-05-15 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer

Also Published As

Publication number Publication date
EP1633394A1 (de) 2006-03-15
JP2006527232A (ja) 2006-11-30
CA2528897A1 (en) 2004-12-16
AU2004244755B2 (en) 2009-06-25
ATE350054T1 (de) 2007-01-15
DE502004002561D1 (de) 2007-02-15
DE10326821A1 (de) 2005-01-05
ES2280972T3 (es) 2007-09-16
EP1633394B1 (de) 2007-01-03
AU2004244755A1 (en) 2004-12-16
AU2004244755B9 (en) 2009-12-24
WO2004108153A1 (de) 2004-12-16

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